Organ transplant tolerance in humans, defined as drug-free long-term allograft function, is rare. Analysis of such unusual cases of successful non-compliance has revealed a pattern of micro-chimerism in blood and the appearance of dendritic-like donor cells in solid tissues. Recently we found that the rare donor cells in the PBL of one such patient have the property of causing highly potent and specific inhibition of donor HLA class I-specific CTL. We hypothesize that donor cells in tolerant patients are highly specialized for inducing anergy in newly arising CD8+ CTL in vivo, without impairing CD4+ T cell direct or indirect pathway responses to donor alloantigens. To test this hypothesis, this proposal seeks to determine: a) if PBL in other tolerant transplant recipients have similar anergic CTL and donor cell mediated veto activity, b) what cellular and molecular mechanisms of donor cell-host T cell interactions give rise to the tolerant phenotype in chimeric kidney and liver graft recipients, and c) whether the pattern of CTL anergy, circulating donor veto cells, and focal lymphoid allograft infiltrates can be used to predict successful withdrawal of steroid immunosuppression. Our study has important implications both for the future of organ transplantation, and for the immunobiology of peripheral tolerance.